Chemokines are small molecular weight (8-12 kDa) secreted polypeptides playing important regulatory role in the immune processes due to their leukocyte attracting (chemotactic) effect. They exert their effects through the chemokine receptors, which belong to the family of the G protein coupled receptors.
The CC chemokine receptors 3 (CCR3 receptors) are expressed by a number of inflammatory cells, like the basofils, mast cells, T lymphocytes, epithelial cells, dendritic cells, but in the greatest amount they can be found on the surface of the eosinofiles.
The CCR3 receptor ligands belong to the family of the C—C kemokines. They have a number of selective and non-selective ligands. The selective ligands are the eotaxin, eotaxin-2 and the lately discovered eotaxin-3. The non-selective ligands are the RANTES, the monocyte chemotactic proteins (MCP-2, MCP-3, MCP-4) and the macrophag inhibitor protein (MIP-1). The best characterized CCR3 ligand known from a long time is the eotaxin.
The eotaxin through the activation of the CCR3 receptors attracts selectively the eosinofils. Prior to an allergen provocation, the measured eotaxin level in the broncho-alveolar lavage fluidum of asthmatic patients was by 67 percent higher. On the effect of provocation a 2.4-fold increase of the epithelial and endothelial cells of the respiratory tract were found.
In the lung the eotaxin is produced in many cells. Following an allergen response, the most important eotaxin sources are the epithelial cells, but a great amount of eotaxin is produced by the fibroblasts of the lung, the smooth muscle cells and the endothelial cells of the respiratory tract, the alveolar macrophags and lymphocytes, and the eosinofils themselves.
Originally the data showed that the CCR3 receptors are to be found only in the eosinofil cells (Bertrand C P, Ponath P D., Expert Opin Investig Drugs. 2000 January; 9(1):43-52.), but on the basis of expression profiles it has been revealed that other inflammatory cells—although in smaller amount—also contain CCR3 receptors (Elsner J, Escher S E, Forssmann U., Allergy. 2004 December; 59(12):1243-58.). Thus, the CCR3 antagonists possess much wider effect, their activity is not limited to the eosinofils and consequently they can be considered much more valuable and effective targets in the treatment of asthmatic, allergic and inflammatory diseases.
Based on the above observations, CCR3 antagonists may possess important profilactic and therapeutic effects in the treatment of pathologies where in the development of the disease CCR3 receptors play a role. These diseases are characterized by the disorder of the leucocyte functions (activation, chemotaxis), there are numerous chronic inflammatory diseases among them, such as asthma, allergic rhinitis, atopic dermatitis, eczema, inflammatory bowel disease, ulcerative colitis, allergic conjunctivitis, arthritis, multiple sclerosis, Crohn's disease, HIV-infection and diseases in conjunction with AIDS.
The CCR3 antagonists published to date in the literature are carbamide-, thiocarbamide derivatives (WO 01/09088, WO 02/059081) and/or compounds containing saturated cyclic amino group (WO 00/35451, U.S. Pat. No. 6,605,623, WO 01/98270, WO 03/004487, WO 03/018556, WO 2004/028530, WO 00/53600, WO 00/35876, WO 01/64216, WO 02/50064, WO 02/102775, GB 2373186, WO 03/082291, WO 2004/004731, WO 2004/058702, WO 2004/085423). The present invention relates to a new structural type of compounds, to the open-chain amino-alkyl-amide derivatives, representatives of these compounds are effective CCR3 receptor antagonists.
From the aspect of therapeutic use it is essential that the molecules do not bind, or bind only in case of very high concentration to other the CCR receptor subtypes.
Our aim was to prepare compounds of high antagonistic activity, and at the same time selective to the CCR3 receptor, i.e. which inhibit the CCR3 receptor in much smaller concentration as compared to other CCR receptors. Further aim was that the new compounds have stability, bioavailability, therapeutic index and toxicity values which ensure its drugability. Additional aim was that the compounds, through their good enteric absorption can be applied orally.